Brain Cancer Stem Cell Reprogramming by c-Met

c-Met 进行脑癌干细胞重编程

• 批准号: 8662816
• 负责人: John J Laterra
• 金额: $ 35万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662816
• 关键词: Address; Animals; Apoptosis; Biology; Brain Neoplasms; Cells; ChIP-on-chip; Clinical; DNA Damage; Data; EGFR inhibition; Excision; Foundations; Gene Expression; Gene Targeting; Genetic Transcription; Glioblastoma; Glioma; Growth; Human; Laboratories; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mesenchymal Stem Cells; Molecular; Mus; Neonatal; Newly Diagnosed; Oncogenic; Pathway interactions; Phenotype; Play; Pluripotent Stem Cells; Property; Publishing; Receptor Protein-Tyrosine Kinases; Recurrence; Relative (related person); Resistance; Role; Signal Pathway; Signal Transduction; Site; Somatic Cell; Stem Cell Development; Stem cells; Testing; Therapeutic; Tumor Cell Line; Tumor Stem Cells; Xenograft procedure; c-myc Genes; cancer cell; cancer stem cell; cancer therapy; clinically relevant; effective therapy; in vivo; inhibitor/antagonist; medulloblastoma; meetings; migration; neoplastic; neoplastic cell; nerve stem cell; novel; novel therapeutics; overexpression; precursor cell; relating to nervous system; research study; stem; stem cell biology; stemness; transcription factor; tumor; tumor growth; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is an almost universally fatal brain tumor with an average median survival of only ~15 months. New effective therapies are desperately needed. Small subpopulations of malignant cells with stem cell-like properties exist in GBM. These neoplastic stem-like cells (GBM SCs) are distinguishable from the majority of tumor cells by their relative resistance to DNA damaging agents, and their ability to efficiently propagate tumor xenografts in experimental animals. GBM SCs are believed to be responsible for GBM resistance to current therapies. The long-term objectives of this proposal are to understand the mechanisms that support GBM SCs since advances in treating GBM will likely depend upon targeting these mechanisms. Specific transcription factors (TFs) such as Sox2, Oct4, and Nanog, have essential roles in maintaining the stemness and proliferation potential of normal neural stem cells. In addition, the forced expression of these and other TFs (e.g. c-Myc, KLF4) can induce or "reprogram" somatic cells into pluripotent stem (iPS) cells. Similarities between iPS cells and GBM SCs suggest our hypothesis that stem cell reprogramming transcription factors and pathways that induce their expression/function play a major role in the formation and/or tumor propagating capacity of GBM SCs. This hypothesis is specifically supported by preliminary data linking oncogenic c-Met signaling to the GBM SC phenotype and the expression of stem cell reprogramming factors. The experiments outlined in this proposal will rigorously examine the c-Met signaling supports the pool of tumor-initiating GBM SCs via transcriptional reprogramming mechanisms. Aim #1 will determine spatial/temporal relationships between the SC phenotype, reprogramming TF expression, and c-Met in newly diagnosed and recurrent GBM. Aim #2 will determine the roles for Oct4 and Nanog in the induction of GBM cell stemness by c-Met. Aim #3 will identify Nanog transcription targets in GBM-CSCs. Aim #4 will determine the effects of in vivo c-Met inhibition on reprogramming mechanisms and GBM cell stemness. These experiments are timely, of high potential impact, and clinically relevant. Positive results will uncover a previously unknown link between stem cell reprogramming mechanisms induced by oncogenic c-Met signaling and the tumor-initiating stem-like phenotype. Results will alter current paradigms regarding neoplastic stem cell biology and provide valuable information for optimizing the clinical development of stem cell targeting brain cancer therapy, and pharmacologic inhibitors of c-Met and other oncogenic reprogramming pathways.

描述（由申请人提供）：胶质母细胞瘤 (GBM) 是一种几乎普遍致命的脑肿瘤，平均中位生存期仅为约 15 个月。迫切需要新的有效疗法。 GBM 中存在具有干细胞样特性的恶性细胞小亚群。这些肿瘤干细胞样细胞 (GBM SC) 与大多数肿瘤细胞的区别在于它们对 DNA 损伤剂的相对抵抗力，以及它们在实验动物中有效繁殖肿瘤异种移植物的能力。 GBM SCs被认为是GBM对当前疗法产生耐药性的原因。该提案的长期目标是了解支持 GBM SC 的机制，因为治疗 GBM 的进展可能取决于针对这些机制。 Sox2、Oct4 和 Nanog 等特定转录因子 (TF) 在维持正常神经干细胞的干性和增殖潜力方面具有重要作用。此外，这些和其他 TF（例如 c-Myc、KLF4）的强制表达可以诱导或“重编程”体细胞为多能干 (iPS) 细胞。 iPS 细胞和 GBM SC 之间的相似性表明我们的假设，即干细胞重编程转录因子和诱导其表达/功能的途径在 GBM SC 的形成和/或肿瘤增殖能力中发挥重要作用。这一假设得到了将致癌 c-Met 信号传导与 GBM SC 表型和干细胞重编程因子表达联系起来的初步数据的具体支持。该提案中概述的实验将严格检查 c-Met 信号通过转录重编程机制支持肿瘤启动 GBM SC 池。目标#1 将确定新诊断和复发 GBM 中 SC 表型、重编程 TF 表达和 c-Met 之间的空间/时间关系。目标 #2 将确定 Oct4 和 Nanog 在 c-Met 诱导 GBM 细胞干性中的作用。目标#3 将识别 GBM-CSC 中的 Nanog 转录靶标。目标 #4 将确定体内 c-Met 抑制对重编程机制和 GBM 细胞干性的影响。这些实验很及时，具有很高的潜在影响，并且具有临床相关性。积极的结果将揭示致癌 c-Met 信号传导诱导的干细胞重编程机制与肿瘤起始干细胞样表型之间以前未知的联系。结果将改变当前关于肿瘤干细胞生物学的范例，并为优化干细胞靶向脑癌治疗以及 c-Met 和其他致癌重编程途径的药理学抑制剂的临床开发提供有价值的信息。